Proliferative Activity of Human Thyroid Cells in Various Age Groups and Its Correlation with the Risk of Thyroid Cancer after Radiation Exposure

Abstract Context: The thyroid gland is vulnerable to the carcinogenic effects of ionizing radiation, and there is a well-documented inverse correlation between thyroid cancer and age at exposure, particularly for ages less than 20 yr. One of the factors responsible for this phenomenon may be more rapid cell proliferation in children. Objective: The objective of this study was to determine the proliferative rate of normal human thyroid cells in different age groups. Design: We used immunohistochemical analysis to determine the Ki-67 proliferative index in 117 thyroid glands obtained at autopsy, including 25 fetal thyroids (11–40 wk gestation), 55 childhood thyroids (0–19 yr), and 37 adult thyroids (20–60 yr). Results: The rate of Ki-67 labeling in the three groups was 7.4 ± 6.10, 0.23 ± 0.15, and 0.08 ± 0.04% respectively, demonstrating an overall trend for diminishing proliferative activity of thyroid cells with increasing age. However, a lack of correlation was noted between the slopes of cancer risk calculated from previous studies of irradiated populations and proliferative rate in the pediatric age intervals of 0–4 and 5–9 yr, suggesting that other factors are likely to be responsible for the particularly high sensitivity to radiation-induced thyroid cancer among the youngest children. Conclusions: Our findings of a general decrease in proliferative activity of thyroid cells with age may explain, at least in part, the higher risks of radiation-related thyroid cancer in children compared with adults. However, the variation in the rate of cell proliferation is unlikely to be responsible entirely for this phenomenon and other factors may also be involved.

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Protein Kinase A-Independent Inhibition of Proliferation and Induction of Apoptosis in Human Thyroid Cancer Cells by 8-Cl-Adenosine

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-2331 ◽

2008 ◽

Vol 93 (3) ◽

pp. 1020-1029 ◽

Cited By ~ 15

Author(s):

Audrey J. Robinson-White ◽

Hui-Pin Hsiao ◽

Wolfgang W. Leitner ◽

Elizabeth Greene ◽

Andrew Bauer ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Thyroid Cancer ◽

Protein Kinase ◽

Protein Kinase A ◽

Cancer Cells ◽

Human Thyroid ◽

Inhibition Of Proliferation ◽

Thyroid Cancer Cells ◽

Kinase A

Abstract Purpose: Protein kinase A (PKA) affects cell proliferation in many cell types and is a potential target for cancer treatment. PKA activity is stimulated by cAMP and cAMP analogs. One such substance, 8-Cl-cAMP, and its metabolite 8-Cl-adenosine (8-Cl-ADO) are known inhibitors of cancer cell proliferation; however, their mechanism of action is controversial. We have investigated the antiproliferative effects of 8-Cl-cAMP and 8-CL-ADO on human thyroid cancer cells and determined PKA’s involvement. Experimental Design: We employed proliferation and apoptosis assays and PKA activity and cell cycle analysis to understand the effect of 8-Cl-ADO and 8-Cl-cAMP on human thyroid cancer and HeLa cell lines. Results: 8-Cl-ADO inhibited proliferation of all cells, an effect that lasted for at least 4 d. Proliferation was also inhibited by 8-Cl-cAMP, but this inhibition was reduced by 3-isobutyl-1-methylxanthine; both drugs stimulated apoptosis, and 3-isobutyl-1-methylxanthine drastically reduced 8-Cl-cAMP-induced cell death. 8-Cl-ADO induced cell accumulation in G1/S or G2/M cell cycle phases and differentially altered PKA activity and subunit levels. PKA stimulation or inhibition and adenosine receptor agonists or antagonists did not significantly affect proliferation. Conclusions: 8-Cl-ADO and 8-Cl-cAMP inhibit proliferation, induce cell cycle phase accumulation, and stimulate apoptosis in thyroid cancer cells. The effect of 8-Cl-cAMP is likely due to its metabolite 8-Cl-ADO, and PKA does not appear to have direct involvement in the inhibition of proliferation by 8-Cl-ADO. 8-Cl-ADO may be a useful therapeutic agent to be explored in aggressive thyroid cancer.

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Oncogene Transformation of PC Cl3 Clonal Thyroid Cell Line Induces an Autonomous Pattern of Proliferation That Correlates with a Loss of Basal and Stimulated Phosphotyrosine Phosphatase Activity*

Endocrinology ◽

10.1210/endo.138.9.5400 ◽

1997 ◽

Vol 138 (9) ◽

pp. 3756-3763 ◽

Cited By ~ 7

Author(s):

Tullio Florio ◽

Antonella Scorziello ◽

Stefano Thellung ◽

Salvatore Salzano ◽

Maria Teresa Berlingieri ◽

...

Keyword(s):

Cell Proliferation ◽

Phosphatase Activity ◽

Cell Lines ◽

Proliferative Activity ◽

Tyrosine Phosphatase ◽

Contact Inhibition ◽

Phosphotyrosine Phosphatase ◽

Thyroid Cells ◽

Transformed Cell ◽

Transformed Cell Lines

Abstract The effects of the stable expression of E1A and/or middle T oncogenes on the proliferative activity of PC Cl3 normal thyroid cells are reported. The proliferation of PC Cl3 cells is mainly regulated by insulin and TSH in a stimulatory way and by somatostatin in an inhibitory fashion. The transformed cell lines, named PC Py and PC E1A Py, show an autonomous pattern of proliferation. The blockade of phosphotyrosine phosphatase activity with vanadate increased the proliferation rate of PC Cl3 under basal and stimulated conditions and completely prevented the inhibitory activity of somatostatin, suggesting that in PC Cl3 cells, a tonic tyrosine phosphatase activity regulates basal and stimulated proliferation, and that a somatostatin-dependent increase in this activity may represent a cytostatic signal. Conversely, in both PC Py and PC E1A Py, vanadate did not modify basal and stimulated proliferation. We analyzed tyrosine phosphatase activity in the different cell lines basally and under conditions leading to the arrest of cell proliferation: confluence (contact inhibition), growth factor deprivation (starvation), and somatostatin treatment. Under basal conditions, tyrosine phosphatase activity was significantly lower in PC Py and PC E1APy cell lines than that in the normal cells. The inhibition of the proliferation induced by contact inhibition or somatostatin treatment was accompanied by an increase in tyrosine phosphatase activity only in PC Cl3 cells. The reduction in tyrosine phosphatase activity in PC E1APy cells correlated with a significant reduction in the expression of R-PTPη, a tyrosine phosphatase cloned from PC Cl3 cells. Conversely, the expression of another receptor-like PTP, PTPμ, was unchanged. Thus, PTPη may be a candidate to mediate inhibitory signals (i.e. activation of somatostatin receptors or cell to cell contact) on the proliferative activity of PC Cl3 cells, and the reduction of its expression in the transformed cell lines may lead to an alteration in the control of cell proliferation.

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Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer

Endocrine Related Cancer ◽

10.1530/erc-13-0399 ◽

2013 ◽

Vol 21 (2) ◽

pp. 161-173 ◽

Cited By ~ 41

Author(s):

Zongjing Zhang ◽

Dingxie Liu ◽

Avaniyapuram Kannan Murugan ◽

Zhimin Liu ◽

Mingzhao Xing

Keyword(s):

Thyroid Cancer ◽

Histone Acetylation ◽

Underlying Mechanism ◽

Histone Deacetylation ◽

Braf V600e ◽

Epigenetic Mechanism ◽

Human Thyroid ◽

Sodium Iodide Symporter ◽

Thyroid Cells ◽

Rat Thyroid

The BRAF V600E mutation causes impaired expression of sodium iodide symporter (NIS) and radioiodine refractoriness of thyroid cancer, but the underlying mechanism remains undefined. In this study, we hypothesized that histone deacetylation at the NIS (SLC5A5) promoter was the mechanism. Using the chromatin immunoprecipitation approach, we examined histone acetylation status on the lysine residues H3K9/14, H3K18, total H4, and H4K16 at the NIS promoter under the influence of BRAF V600E. We found that expression of stably or transiently transfected BRAF V600E inhibited NIS expression while the deacetylase inhibitor SAHA stimulated NIS expression in PCCL3 rat thyroid cells. Although BRAF V600E enhanced global histone acetylation, it caused histone deacetylation at the NIS promoter while SAHA caused acetylation in the cells. In human thyroid cancer BCPAP cells harboring homozygous BRAF V600E mutation, BRAF V600E inhibitor, PLX4032, and MEK inhibitor, AZD6244, increased histone acetylation of the NIS promoter, suggesting that BRAF V600E normally maintained histone in a deacetylated state at the NIS promoter. The regions most commonly affected with deacetylation by BRAF V600E were the transcriptionally active areas upstream of the translation start that contained important transcription factor binding sites, including nucleotides −297/−107 in the rat NIS promoter and −692/−370 in the human NIS promoter. Our findings not only reveal an epigenetic mechanism for BRAF V600E-promoted NIS silencing involving histone deacetylation at critical regulatory regions of the NIS promoter but also provide further support for our previously proposed combination therapy targeting major signaling pathways and histone deacetylase to restore thyroid gene expression for radioiodine treatment of thyroid cancer.

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Cl-IB-MECA inhibits human thyroid cancer cell proliferation independently of A3 adenosine receptor activation

Cancer Biology & Therapy ◽

10.4161/cbt.7.2.5301 ◽

2008 ◽

Vol 7 (2) ◽

pp. 278-284 ◽

Cited By ~ 40

Author(s):

Silvana Morello ◽

Antonello Petrella ◽

Michela Festa ◽

Ada Popolo ◽

Mario Monaco ◽

...

Keyword(s):

Cell Proliferation ◽

Thyroid Cancer ◽

Cancer Cell ◽

Adenosine Receptor ◽

Receptor Activation ◽

Human Thyroid ◽

Cancer Cell Proliferation ◽

Thyroid Cancer Cell ◽

A3 Adenosine Receptor ◽

Adenosine Receptor Activation

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Effect of low-dose tungsten on human thyroid stem/precursor cells and their progeny

Endocrine Related Cancer ◽

10.1530/erc-19-0176 ◽

2019 ◽

Vol 26 (8) ◽

pp. 713-725 ◽

Cited By ~ 3

Author(s):

Fiorenza Gianì ◽

Giuseppe Pandini ◽

Nunzio Massimo Scalisi ◽

Paolo Vigneri ◽

Carmine Fazzari ◽

...

Keyword(s):

Thyroid Cancer ◽

Chronic Exposure ◽

Low Dose ◽

Biological Effects ◽

Precursor Cells ◽

Mount Etna ◽

Human Thyroid ◽

Volcanic Area ◽

Thyroid Cells

Thyroid cancer incidence is increased in volcanic areas where environment pollution biocontaminates residents. Tungsten (W) is the most increased heavy metal in drinking water of Mount Etna volcanic area where it exceeds the normal range in the urine of 27% inhabitants. The possible connection between increased tungsten and thyroid cancer has never been studied. We investigated in vitro the effect tungsten on both human thyrocytes in primary culture, thyrospheres (aggregates of stem/precursor thyroid cells) and thyrocytes differentiated from tungsten-exposed thyrospheres. Chronic exposure to low-dose (nanomolar range, as in the urines of volcanic area residents) soluble tungsten had major biological effects on thyroid stem/precursor cells, promoting growth with a biphasic (hormetic) dose-response and reducing apoptosis. No such effects were observed in mature thyrocytes. In addition, tungsten-exposed thyrospheres had abnormal expression of genes commonly altered also in thyroid cancer and increased activation of the DNA-repair proteins H2AX and 53BP1. Moreover, exposure to tungsten decreased thyrosphere differentiation, as indicated by the reduced expression of thyroid-specific genes in derived thyrocytes that also showed preneoplastic changes such as increased anchorage-independent growth, clonogenic growth and migration capacity. The mechanism of action of tungsten on thyroid stem/precursor cells is unclear but involves membrane G-proteins and activation of the ERK signaling pathway. These data indicate that chronic exposure to slightly increased tungsten, harmless for mature thyrocytes, importantly affects the biology of stem/precursor thyroid cells and of their progeny, inducing characteristics of preneoplastic transformation.

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Immunohistochemical characteristics of breast cancer, increasing the risk of local reccurence after organosaving treatment

Tumors of female reproductive system ◽

10.17650/1994-4098-2018-14-3-10-14 ◽

2018 ◽

Vol 14 (3) ◽

pp. 10-14

Author(s):

S. M. Demidov ◽

D. A. Demidov ◽

S. V. Sazonov ◽

E. I. Churakova

Keyword(s):

Breast Cancer ◽

Proliferative Activity ◽

Receptor Gene ◽

Molecular Genetic ◽

Statistical Processing ◽

Immunohistochemical Analysis ◽

Recurrent Tumor ◽

Ki 67 ◽

Epidermal Growth ◽

Triple Negative Subtype

Objective:an immunohistochemical analysis of the characteristics of a recurrent tumor in breast cancer.Materials and methods.The statistical processing of immunohistochemical analysis’ results was performed and the most frequently encountered molecular-genetic subtypes of breast cancer with the development of local relapses were formulated. The analysis used a standard immunohistochemical panel, which is the “gold standard” for diagnostic in Russia today, and includes the expression of receptors for sex hormones (estrogen and progesterone), expression of the human epidermal growth factor HER2/neu receptor gene, and the index of proliferative activity Ki-67. The 2nd stage of the work was the evaluation of the dynamics of changes in the immunohistochemical characteristics of a recurrent tumor in comparison with the primary one.Results and conclusion.The most common local recurrence provides by triple-negative subtype of breast cancer (42 %). The changes in the immunohistochemical characteristics of a recurrent tumor in comparison with the primary one affected only the index of proliferative activity Ki-67 in the direction of its increase by 12 %.

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Thyroid Stem Cells But Not Differentiated Thyrocytes Are Sensitive to Slightly Increased Concentrations of Heavy Metals

Frontiers in Endocrinology ◽

10.3389/fendo.2021.652675 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fiorenza Gianì ◽

Roberta Masto ◽

Maria Antonietta Trovato ◽

Annarita Franco ◽

Giuseppe Pandini ◽

...

Keyword(s):

Heavy Metals ◽

Thyroid Cancer ◽

Response Curve ◽

Living Cells ◽

Human Thyroid ◽

Target Cells ◽

Volcanic Area ◽

Thyroid Cells ◽

Biphasic Pattern ◽

Thyroid Cancer Incidence

Thyroid cancer incidence is markedly increased in volcanic areas where residents are biocontaminated by chronic lifelong exposure to slightly increased metals in the environment. Metals can influence the biology of living cells by a variety of mechanisms, depending not only on the dose and length of exposure but also on the type and stage of differentiation of target cells. We explored the effect of five heavy metals (Cu, Hg, Pd, W and Zn) at nanomolar concentrations (the biocontamination level in residents of the volcanic area in Sicily where thyroid cancer is increased) on stimulating the proliferation of undifferentiated (thyrospheres) and differentiated human thyroid cells. Thyrosphere proliferation was significantly increased after exposure to each individual metal and a greater stimulating effect was observed when a mixture of the examined metals was used. No effect was seen in differentiated thyrocytes. For all metals, the dose-response curve followed a biphasic pattern that is typical of hormesis. Thyrosphere growth concerned the size rather than number, except with the metal mixture. An altered morphology was also observed in metal-treated thyrospheres. Metal-induced proliferation was due to activation of the ERK1/2 pathway, as confirmed by growth inhibition when ERK1/2 signaling was blocked. These studies show that stem/precursor thyroid cells are sensitive to small increases in environmental metal concentrations that are harmless for differentiated thyrocytes.

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